PDX1 (pancreatic and duodenal homeobox 1), also known as insulin promoter factor 1, is a transcription factor necessary for pancreatic development, including β-cell maturation, and duodenal differentiation. In humans this protein is encoded by the PDX1 gene, which was formerly known as IPF1.[1][2]
In pancreatic development, Pdx1 is expressed by a population of cells in the posteriorforegut region of the definitive endoderm, and Pdx1+epithelial cells give rise to the developing pancreatic buds, and eventually, the whole of the pancreas—its exocrine, endocrine, and ductal cell populations.[3] Pancreatic Pdx1+ cells first arise at mouse embryonic day 8.5-9.0 (E8.5-9.0), and Pdx1 expression continues until E12.0-E12.5,[4] after which Pdx1 expression decreases and the pancreas is formed—other transcription factors are expressed, controlling the fates of the cells of the newly formed pancreas.[5] Homozygous Pdx1 knockout mice form pancreatic buds but fail to develop a pancreas,[5] and transgenic mice in which tetracycline application results in death of Pdx1+ cells are almost completely apancreatic if doxycycline (tetracycline derivative) is administered throughout the pregnancy of these transgenic mice, illustrating the necessity of Pdx1+ cells in pancreatic development.[4]
β-cell maturation and survival
Pdx1 is also necessary for β-cell maturation: developing β-cells co-express Pdx1, NKX6-1, and insulin, a process that results in the silencing of MafB and the expression of MafA, a necessary switch in maturation of β-cells.[3] Pdx1 appears to also play a role in the fating of endocrine cells, encoding for insulin and somatostatin, two pancreatic endocrine products, while repressing glucagon. Thus, Pdx1 expression apparently favors the production of insulin+ β-cells and somatostatin+Δ-cells rather than glucagon+ α-cells. In addition to roles in beta-cell differentiation, Pdx1 is required for β-cell survival. Cells with reduced Pdx1 have an increased rate of apoptotic programmed cell death.[6][7]
Transcriptional network
Pdx1+pancreatic progenitor cells also co-express Hlxb9, Hnf6, Ptf1a and NKX6-1, and these progenitor cells form the initial pancreatic buds, which further proliferate and branch in response to FGF-10 signaling. Afterwards, fating of the pancreatic cells begins; a population of cells has Notch signaling inhibited, and subsequently, expresses Ngn3. This Ngn3+ population is a transient population of pancreatic endocrine progenitors that gives rise to the α, β, Δ, PP, and ε cells of the islets of Langerhans.[4] Other cells will give rise to the exocrine and ductal pancreatic cell populations.
Duodenum
Pdx1 is necessary for the development of the proximal duodenum and maintenance of the gastro-duodenal junction.[8] Duodenal enterocytes, Brunner's glands and entero-endocrine cells (including those in the gastric antrum) are dependent on Pdx1 expression. It is a ParaHox gene, which together with Sox2 and Cdx2, determines the correct cellular differentiation in the proximal gut.[8] In mature mice duodenum, several genes have been identified which are dependent on Pdx1 expression and include some affecting lipid and iron absorption.[9]
↑Stoffel M, Stein R, Wright CV, Espinosa R, Le Beau MM, Bell GI (July 1995). "Localization of human homeodomain transcription factor insulin promoter factor 1 (IPF1) to chromosome band 13q12.1". Genomics. 28 (1): 125–6. doi:10.1006/geno.1995.1120. PMID7590740.
↑ 3.03.1D'Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG, Moorman MA, Kroon E, Carpenter MK, Baetge EE (November 2006). "Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells". Nat. Biotechnol. 24 (11): 1392–401. doi:10.1038/nbt1259. PMID17053790.
↑ 4.04.14.2Stanger BZ, Tanaka AJ, Melton DA (February 2007). "Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver". Nature. 445 (7130): 886–91. doi:10.1038/nature05537. PMID17259975.
↑ 8.08.1Holland AM, Garcia S, Naselli G, Macdonald RJ, Harrison LC (2013). "The Parahox gene Pdx1 is required to maintain positional identity in the adult foregut". Int. J. Dev. Biol. 57 (5): 391–8. doi:10.1387/ijdb.120048ah. PMID23873371.
↑Fajans SS, Bell GI, Polonsky KS (September 2001). "Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young". N. Engl. J. Med. 345 (13): 971–80. doi:10.1056/NEJMra002168. PMID11575290.
↑Ma J, Chen M, Wang J, Xia HH, Zhu S, Liang Y, Gu Q, Qiao L, Dai Y, Zou B, Li Z, Zhang Y, Lan H, Wong BC (2008). "Pancreatic duodenal homeobox-1 (PDX1) functions as a tumor suppressor in gastric cancer". Carcinogenesis. 29 (7): 1327–33. doi:10.1093/carcin/bgn112. PMID18477649.
↑Zhao L, Guo M, Matsuoka TA, Hagman DK, Parazzoli SD, Poitout V, Stein R (March 2005). "The islet beta cell-enriched MafA activator is a key regulator of insulin gene transcription". J. Biol. Chem. 280 (12): 11887–94. doi:10.1074/jbc.M409475200. PMID15665000.
Further reading
Zhou Q, Brown J, Kanarek A, Rajagopal J, Douglas A & Melton DA (2008). "In vivo reprogramming of adult pancreatic exocrine cells to β-cells". Nature. 455 (7213): 627–32. doi:10.1038/nature07314. PMID18754011.
Hui H, Perfetti R (2002). "Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood". Eur. J. Endocrinol. 146 (2): 129–41. doi:10.1530/eje.0.1460129. PMID11834421.
Leonard J, Peers B, Johnson T, et al. (1994). "Characterization of somatostatin transactivating factor-1, a novel homeobox factor that stimulates somatostatin expression in pancreatic islet cells". Mol. Endocrinol. 7 (10): 1275–83. doi:10.1210/me.7.10.1275. PMID7505393.
Stoffel M, Stein R, Wright CV, et al. (1995). "Localization of human homeodomain transcription factor insulin promoter factor 1 (IPF1) to chromosome band 13q12.1". Genomics. 28 (1): 125–6. doi:10.1006/geno.1995.1120. PMID7590740.
Inoue H, Riggs AC, Tanizawa Y, et al. (1996). "Isolation, characterization, and chromosomal mapping of the human insulin promoter factor 1 (IPF-1) gene". Diabetes. 45 (6): 789–94. doi:10.2337/diabetes.45.6.789. PMID8635654.
Waeber G, Thompson N, Nicod P, Bonny C (1997). "Transcriptional activation of the GLUT2 gene by the IPF-1/STF-1/IDX-1 homeobox factor". Mol. Endocrinol. 10 (11): 1327–34. doi:10.1210/me.10.11.1327. PMID8923459.
Watada H, Kajimoto Y, Kaneto H, et al. (1997). "Involvement of the homeodomain-containing transcription factor PDX-1 in islet amyloid polypeptide gene transcription". Biochem. Biophys. Res. Commun. 229 (3): 746–51. doi:10.1006/bbrc.1996.1875. PMID8954967.
Stoffers DA, Zinkin NT, Stanojevic V, et al. (1997). "Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence". Nat. Genet. 15 (1): 106–10. doi:10.1038/ng0197-106. PMID8988180.
Carty MD, Lillquist JS, Peshavaria M, et al. (1997). "Identification of cis- and trans-active factors regulating human islet amyloid polypeptide gene expression in pancreatic beta-cells". J. Biol. Chem. 272 (18): 11986–93. doi:10.1074/jbc.272.18.11986. PMID9115263.
Macfarlane WM, Smith SB, James RF, et al. (1997). "The p38/reactivating kinase mitogen-activated protein kinase cascade mediates the activation of the transcription factor insulin upstream factor 1 and insulin gene transcription by high glucose in pancreatic beta-cells". J. Biol. Chem. 272 (33): 20936–44. doi:10.1074/jbc.272.33.20936. PMID9252422.
Glick E, Leshkowitz D, Walker MD (2000). "Transcription factor BETA2 acts cooperatively with E2A and PDX1 to activate the insulin gene promoter". J. Biol. Chem. 275 (3): 2199–204. doi:10.1074/jbc.275.3.2199. PMID10636926.
Schwartz PT, Perez-Villamil B, Rivera A, et al. (2000). "Pancreatic homeodomain transcription factor IDX1/IPF1 expressed in developing brain regulates somatostatin gene transcription in embryonic neural cells". J. Biol. Chem. 275 (25): 19106–14. doi:10.1074/jbc.M000655200. PMID10751390.
Liu Y, MacDonald RJ, Swift GH (2001). "DNA binding and transcriptional activation by a PDX1.PBX1b.MEIS2b trimer and cooperation with a pancreas-specific basic helix-loop-helix complex". J. Biol. Chem. 276 (21): 17985–93. doi:10.1074/jbc.M100678200. PMID11279116.
Zhou J, Pineyro MA, Wang X, et al. (2002). "Exendin-4 differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX-1 and HNF3beta transcription factors". J. Cell. Physiol. 192 (3): 304–14. doi:10.1002/jcp.10143. PMID12124776.
